TY - JOUR
T1 - Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions
AU - Fujikura, Kohei
AU - Hosoda, Waki
AU - Felsenstein, Matthäus
AU - Song, Qianqian
AU - Reiter, Johannes G.
AU - Zheng, Lily
AU - Beleva Guthrie, Violeta
AU - Rincon, Natalia
AU - Dal Molin, Marco
AU - Dudley, Jonathan
AU - Cohen, Joshua D.
AU - Wang, Pei
AU - Fischer, Catherine G.
AU - Braxton, Alicia M.
AU - Noë, Michaël
AU - Jongepier, Martine
AU - Fernández-Del Castillo, Carlos
AU - Mino-Kenudson, Mari
AU - Schmidt, C. Max
AU - Yip-Schneider, Michele T.
AU - Lawlor, Rita T.
AU - Salvia, Roberto
AU - Roberts, Nicholas J.
AU - Thompson, Elizabeth D.
AU - Karchin, Rachel
AU - Lennon, Anne Marie
AU - Jiao, Yuchen
AU - Wood, Laura D.
N1 - Publisher Copyright:
© 2021 Author(s).
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Objective Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. Design We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. Results Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. Conclusion Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
AB - Objective Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. Design We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. Results Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. Conclusion Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
KW - molecular genetics
KW - mutations
KW - pancreatic cancer
KW - pancreatic pathology
KW - pancreatic tumours
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U2 - 10.1136/gutjnl-2020-321217
DO - 10.1136/gutjnl-2020-321217
M3 - Article
C2 - 33028669
AN - SCOPUS:85096445322
SN - 0017-5749
VL - 70
SP - 928
EP - 939
JO - Gut
JF - Gut
IS - 5
ER -